The frequency of JAK2 exon 12 mutations in idiopathic erythrocytosis patients with low serum erythropoietin levels.

Background and Objectives: Idiopathic erythrocytosis (IE) is characterized by erythrocytosis in the absence of megakaryocytic or granulocytic hyperplasia, and is associated with variable serum erythropoietin (Epo) levels. Most patients with IE lack the JAK2 V617F mutation that occurs in the majority of polycythemia vera patients. Four novel JAK2 mutant alleles have recently been described in patients with V617F-negative myeloproliferative disorders presenting with erythrocytosis. The aims of this study were to assess the prevalence of JAK2 exon 12 mutations in IE patients, and to determine the associated clinicopathological features.
Design and Methods: A cohort of 58 IE patients with low to normal serum Epo levels and no known causative mutation were identified from 181 individuals diagnosed with IE. Patients' DNA samples were screened for the presence of a JAK2 exon 12 mutation by allele-specific polymerase chain reaction and sequencing. Bone marrow trephines were examined for morphological abnormalities and the erythroid activity assessed immunohistochemically.
Results: Eight mutation-positive cases were identified, including one with a previously undescribed mutant JAK2 exon 12 allele and another with biallelic involvement. The hematologic features of mutation-positive and mutation-negative patients were similar, although Epo-hypersensitive erythroid progenitors occurred exclusively in patients with an exon 12 mutation (p=0.0002; n=15). Patients' bone marrows were moderately hypercellular, as the result of erythroid hyperplasia, and several had mild megakaryocyte atypia.
Interpretation and Conclusions: JAK2 exon 12 mutations were detected in 27% of patients with low serum Epo levels, all of whom had Epo-independent erythroid progenitors. Consequently, IE patients presenting with either of these features should be tested for the presence of a JAK2 mutation.